Targeting DNA mismatch repair for radiosensitization

Postreplicational mismatch repair (MMR) proteins are capable of recognizing and processing not only single base-pair mismatches and insertion-deletion loops (IDLs) that occur during DNA replication, but also adducts in DNA resulting from treatment with cancer chemotherapy agents. These include widely varying types of DNA adducts resulting from methylating agents such as MNNG, MNU, temozolomide, and procarbazine; CpG crosslinks resulting from cisplatin and carboplatin; and S(6)-thioguanine and S(6)-methylthioguanine residues in DNA. Although MMR proteins can recognize both replicational errors and chemotherapy-induced adducts in DNA, the end results of this recognition are very different. Base-base mismatches and IDLs can be repaired by MMR, restoring genomic integrity, whereas MMR-mediated recognition and processing of chemotherapy-induced adducts in DNA results in apoptosis. After the loss of MMR, the inability of cells to recognize and correct single base-pair mismatches and insertion-deletion loops can lead to secondary mutations in proto-oncogenes and tumor-suppressor genes, thereby contributing to the development of cancer. In addition, the inability of MMR-deficient cells to recognize chemotherapy-induced adducts in DNA can result in a damage-tolerant phenotype that translates to clinically significant resistance by allowing for selection of MMR-deficient cancer cells. We have shown recently that these MMR-deficient, drug-resistant cells can be targeted for radiosensitization by the halogenated thymidine analogs iododeoxyuridine (IdUrd) and bromodeoxyuridine (BrdUrd). These thymidine (dThd) analogs become incorporated into DNA and form reactive uracil radicals after ionizing radiation (IR), increasing strand breaks. IdUrd and BrdUrd appear to be removed from DNA in MMR-proficient cells with limited toxicity or disruption of the cell cycle, while accumulating at much higher levels in MMR-deficient cells. As a result, it is possible to effectively increase the radiosensitization of MMR-deficient cells at levels of halogenated dThd analog that demonstrate limited toxicity to MMR-proficient cells. This indicates that a combined approach of IdUrd or BrdUrd with IR may be effective in killing MMR-deficient tumors in patients, which are resistant to many cancer chemotherapy agents commonly used in the clinic.